A twist for survival and cancer progression

Abstract

A major obstacle to the expansion of abnormal cells with significant proliferative potential is the induction of programmed cell death. Consequently, oncogene-driven hyperproliferation must be associated with apoptosis inhibition to allow malignant outgrowth. The oncogenic cooperation of N-Myc and Twist-1 in the development of neuroblastoma, the most common and deadly solid tumour of childhood, perfectly illustrates such a process. N-Myc promotes cell proliferation, whereas Twist-1 counteracts its pro-apoptotic properties by knocking-down the ARF/p53 pathway. On the basis of numerous recent studies reporting its overexpression in a variety of human cancers, we discuss in this review the role of Twist-1 as a potent inhibitor of the cell safety programs engaged in response to an abnormal mitogenic activity.

Figure 1

Functional domains of human Twist-1 and Twist-2 proteins. The glycine-rich region is specific to Twist-1. The Runx2-binding ‘Twist box’ has been implicated in the antiosteogenic function of Twist-1 and Twist-2 (Bialek et al, 2004).

Figure 2

Twist-1 as a potent inhibitor of p53 tumour suppressor activity. Twist inhibits p53-mediated response to cellular stress (activated oncogenes or DNA damage) by modulating both ARF expression and p53 post-translational modifications such as phosphorylation and acetylation.